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At least 19 recordsLinked to original sources
PubMed1992

Investigation of the mutagenic activity in Salmonella typhimurium of the furochromone khellin, proposed as a therapeutic agent for skin diseases.

The photomutagenicity of the furochromone khellin was tested in Ames Salmonella strains using 8-methoxypsoralen (8-MOP) and 4,5', 8-trimethylpsoralen (TMP) as positive controls. When khellin was assayed with strain TA1537, mutation induction was not detectable; in the same strain, an equitoxic dose (52-56% level of survival) of TMP (used at a concentration 12-fold lower than khellin and with a UVA dose 83-fold lower than that used with khellin) yielded an increase in revertants/plate 3-fold above the spontaneous background. In strain TA102, khellin plus UVA treatment yielded a 2-fold increase in revertants/plate above the spontaneous background (79% survival). 8-MOP, however, used at a concentration 8-fold lower than khellin with a UVA dose 13-fold lower than khellin, yielded an increase in revertants/plate about 14-fold above background (66% survival) in the same strain. These data show that khellin has a weak photomutagenic potential and, along with the previously reported low photogenotoxic potential in eukaryotic cell systems, support the notion that khellin may be safer than bifunctional psoralens for clinical use.

Khellin↗
PubMedDate not supplied

Treatment with topical khellin in combination with ultraviolet A or solar-simulated radiation is carcinogenic to lightly pigmented hairless mice.

Khellin is used together with either UVA irradiation or sun exposure in the treatment of vitiligo. The purpose of this study was to investigate the carcinogenic effect of topically applied khellin together with UVA or solar simulated radiation (SSR) in lightly pigmented C3H/Tif mice. For comparison purposes a 0.1% 8-methoxypsoralen (8-MOP) cream was also tested in combination with SSR. Fifty microliters of a 5% khellin cream, a 0.1% 8-MOP cream, or a cream without active substances were spread uniformly on the back of the mice 30 minutes before UVA or SSR irradiation. All mice were irradiated 3 times a week until age or skin tumor development necessitated killing. Treatment with topical khellin and UVA irradiation was carcinogenic to lightly pigmented hairless mice, time to 50% of the mice had developed one tumor (t50) was 507 days. This indicates that the combination of topical khellin and UVA radiation, formerly expected to be rather innocuous, is carcinogenic to mice. Also the combination of khellin and SSR (t50 = 268 days) enhanced skin tumor development significantly compared with control cream and SSR (t50 = 330 days), P < 0.05. In addition, the combination of khellin and SSR was found to have the same carcinogenic effect as treatment with 0.1% 8-MOP and SSR (t50 = 262 days). This study shows that topically applied khellin increases the carcinogenic effect of both UVA and sunlight.

Administration, Topical↗
PubMed1985

Hypocholesterolemic effect of khellin and khelloside in female cynomolgus monkeys.

Khellin and khelloside (khellol glucoside) were examined in female cynomolgus monkeys to substantiate their ability to favorably modify serum lipoprotein cholesterol. Clinical chemistry parameters were also measured to obtain information indicative of possible drug toxicity. Both drugs were evaluated in two week multiple-dose studies and after a single oral dose. After two weeks at 20 mg/kg per day, khellin and khelloside significantly lowered low density lipoprotein cholesterol (LDL-C) by 87% and 73%, high density lipoprotein cholesterol (HDL-C) by 41% and 23%, and total-C by 55% and 44%, respectively. Very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) were not changed. No apparent toxicity was observed as clinical chemistry parameters and body weights were not different compared to control values. Similar results were observed with lower doses of khellin and khelloside. Khellin at 5 mg/kg per day reduced LDL-C by 50%, HDL-C by 15%, and total-C by 30%, while khellol glucoside at 10 mg/kg per day lowered LDL-C by 46%, HDL-C by 20%, and total-C by 31%. Neither drug produced significant changes in VLDL-C, TG, body weights, or clinical chemistry variables. A 2 mg/kg per day dose of khellin also had no observable effect in this study. Single oral doses (20 mg/kg) of khellin and khelloside caused modulation of LDL-C (-32% and -30%) and total-C (-18% and -15%). Visual observation of the monkeys during this study revealed that khellin caused emesis in 9/9 animals, while khelloside and control had no emetic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Genetic effects of photoadducts and photocross-links in the DNA of phage lambda exposed to 360 nm light and tri-methylpsoralen or khellin.

The furocoumarin, 4,5',8-trimethylpsoralen, sensitizes cells and viruses to 360 nm light, producing cross-links and monoadducts in their DNA. The furanochromone khellin is a less effective sensitizing agent than psoralen, but has been found to induce cross-links and adducts in DNA also. The number of cross-links increases as the square of the time of exposure to light. We found that greater fluences were required for khellin than for psoralen, possibly because of the less favorable angle of the distal unsaturated bonds for corss-linking pyrimidines in adjacent base pairs. By adjusting the time of exposure to 360 nm light, lambda phages were damaged with [3H]psoralen and [3H]khellin so as to produce equal numbers of cross-links. These exposures were found to produce 8-times more [3H]khellin than [3H]psoralen adducts in the DNA of the phages. Similar exposures were made with nonradioactive photosensitizers to determine the effectiveness of lambda phages carrying cross-links and monoadducts in producing genetic recombinants. Lambda phage-prophage genetic corsses were performed with psoralen and khellin-damaged phages under repressed conditions in which replication of the damaged DNA was blocked. It was estimated from the results that cross-links were about 20-times more effective than monoadducts for inducing recombination under repressed conditions. In tests on the survival of plaque forming ability on wild type bacteria, it was estimated that cross-links were about 15-times more effective than the adducts. The results support the conclusion that, in homoimmune crosses with psoralen-damaged lambda phages infecting wild type lysogens, more than three-quarters of the induced recombination can be attributed to cross-links rather than to monoadducts.

Binding Sites↗
PubMed1999

Distribution of khellin in excised human skin following iontophoresis and passive dermal transport.

The aim of this work was to study in vitro khellin distribution into human skin after passive or iontophoretic transport. The experiments were performed on excised human skin, using vertical Franz-type diffusion cells. The effects of current application and reservoir pH were studied. At the end of the experiments the skin was sliced thinly and the drug was extracted and analyzed by HPLC. The results showed that khellin is able to penetrate through stratum corneum, to reach basal epidermis and upper dermis. The application time proved to be an important parameter. Current application (30 min; 0.5 mA/cm(2)), with a donor at pH 7.0, favored khellin accumulation even if the drug is not ionized. On the contrary, the use of a formulation at pH 3.2 inhibited drug accumulation. Leaving the drug reservoir in contact with the skin for 30 min after current application led to a dramatic increase of khellin concentration. A combination of dermal iontophoresis and passive diffusion is then a useful technique to govern khellin distribution in the skin.

Chromatography, High Pressure Liquid↗
PubMed1988

Treatment of vitiligo with khellin and ultraviolet A.

Twenty-eight patients with vitiligo were treated with a new photochemotherapeutic regimen using khellin, a furanochromone, as photosensitizer, together with ultraviolet A (UVA) irradiation. Twenty-five patients received khellin orally and three patients were treated with topical khellin. Treatments were given three times weekly. As opposed to psoralens, khellin did not induce skin phototoxicity with UVA but it induced repigmentation similar to psoralens. The treatment success strongly depended on the number of treatments. More than 70% repigmentation was achieved in 41% of the patients who had received 100 to 200 treatments. This success rate is comparable to the rate obtained with psoralens. Seven patients experienced a mild elevation of liver transaminases within the early treatment phase and their treatments were discontinued. No long-term internal organ or skin toxicity was observed. The major advantage of khellin is that it does not lead to phototoxic skin erythema and thus can be considered safe for home treatment. Because of its photochemistry it may be considered less hazardous than psoralens regarding mutagenicity and carcinogenicity.

Adolescent↗
PubMed1989

Relaxant actions of khellin on vascular smooth muscle.

To clarify the mechanism of the vasodilatory action of khellin on calcium, we have investigated its relaxant action on base line and on K+ and noradrenaline-induced contractile tensions in rat aorta smooth muscle and on spontaneous contractile activity of rat portal vein. Khellin relaxed both of these preparations with a similar potency, which suggests a non-specific inhibition of calcium flux, without any difference related to the specific calcium channels. We have also studied the capacity of khellin to interfere with the loading and release mechanisms of caffeine and noradrenaline-sensitive calcium stores in Ca-free medium. Khellin's Ca2+ loading reduction may be related with its capacity to inhibit calcium influx. Khellin applied during Ca2+ release also caused relaxation. We propose that this drug may enhance calcium extrusion or sequestration rather than the calcium release mechanism. These actions on calcium influx and intracellular mobilization can contribute to its vasorelaxant action.

Animals↗
PubMed1992

Photochemotherapy with topical khellin and sunlight in vitiligo.

In order to evaluate the efficacy of topical khellin the vitiligo macules of one side only were painted in 41 patients with a 2% solution of khellin in acetone and propylene glycol (90 and 10%, respectively) and exposed to sunlight for a period of 4 months with 3 weekly applications and with exposure times up to 90 min. The macules of the other side were treated in 36 of the 41 patients with acetone and propylene glycol only and sun-exposed with the same schedule, while in the remaining 5 patients they were neither treated with khellin or placebo nor sun-exposed. No significant difference was evidenced between the khellin and placebo-treated sides: no excellent result (repigmentation more than 75% of the affected area) was found, and good results (repigmentation more than 50%) were found in 24.9% of khellin- plus sunlight-treated macules and in 22.3% of placebo- plus sunlight-treated macules.

Administration, Topical↗
PubMed1990

High performance liquid chromatographic determinations of khellin, phenobarbitone and dipyrone combination in tablets.

High performance liquid chromatographic methods for the individual determination of khellin, phenobarbitone and dipyrone in tablets are presented. The methods specify a reverse phase column: methanol + water (68 + 32) as mobile phase at a flow rate of 0.7 ml/min with detection at 254 nm for khellin, visgnagin and dipyrone; water + ammonia + methanol (94.5 + 0.5 + 5) as a mobile phase at a flow rate of 0.7 ml/min with detection at 240 nm for phenobarbitone. At sensitivity of 0.01 AUFS, linearity ranges were found to be 0.5-4 micrograms/ml for khellin, 2.5-12.5 micrograms/ml for dipyrone and 1-7 micrograms/ml for phenobarbitone and with relative standard deviations less than 2%. The mean percentage recoveries +/- SD of khellin, dipyrone and phenobarbitone added to tablets were found to be 101.0 +/- 0.65, 100.0 +/- 0.74 and 99.9 +/- 0.74, respectively. The system can detect 2% w/w visnagin in khellin.

Aminopyrine↗
PubMed1992

Improved high-performance liquid chromatographic determination of khellin and visnagin in Ammi visnaga fruits and pharmaceutical formulations.

An improved, simple, selective, and sensitive reversed-phase high-performance liquid chromatographic (HPLC) assay for khellin and visnagin in Ammi visnaga L. fruits was developed by using an internal standardized technique. The HPLC column was a reversed-phase microBondapack C18 column, the mobile phase was water: methanol:acetonitrile (49:49:2), and the flow rate was 1.5 mL/min. Khellin and visnagin were detected and analyzed with a spectrophotometer set at 250 nm. Results of the HPLC analysis indicate a relative standard deviation of less than 0.04%. The analytical procedure was used for the quantification of khellin in various pharmaceutical dosage forms, such as ampules, tablets, and suppositories, with relative standard deviations of 1.2, 1.4, and 1.7%, respectively. As little as 10 ng of khellin or visnagin could be detected accurately in less than 13 min.

Calibration↗
PubMed1991

Effects of khellin on contractile responses and 45Ca2+ movements in rat isolated aorta.

The effects of khellin on contractile responses and 45Ca2+ flux have been studied in rat isolated aortae. Khellin (10(-5)-3.2 x 10(-4) M) produced a concentration-dependent inhibition of noradrenaline (10(-6) M) and high K+ (80 mM)-induced contractions. At 3.2 x 10(-4) M, khellin increased cAMP levels and reduced 45Ca2+ influx in resting tissues and in tissues stimulated by noradrenaline (10(-5) M) and high K+ without affecting basal 45Ca2+ efflux or noradrenaline induced 45Ca2+ efflux. It is concluded that in rat isolated aorta, khellin caused a non-specific inhibition of Ca2+ influx but may also exhibit intracellular actions, thus decreasing the availability of Ca2+ required for activation. One or more of these mechanisms may be related to an increase in intracellular cAMP levels.

Animals↗